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`J Ophthalmic Vis Res. 2014 Apr; 9(2): 240–250.
`
`PMCID: PMC4181208
`
`Dry Eye: an Inflammatory Ocular Disease
`Michelle Hessen, OD and Esen Karamursel Akpek, MD
`
`Ocular Surface Diseases & Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
`Correspondence to: Esen Karamursel Akpek, MD. Ocular Surface Diseases & Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins School
`of Medicine, Baltimore, Maryland, USA; Tel: +1 410 955 5214, Fax: +1 410 614 6480; email:
`ude.imhj@kepkase
`
`Received 2014 Mar 17; Accepted 2014 Apr 13.
`
`Copyright © 2014 Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences
`
`This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy,
`distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited
`properly.
`
`This article has been cited by other articles in PMC.
`
`Go to:
`
`Abstract
`Keratoconjunctivitis sicca, or dry eye, is a common ocular disease prompting millions of individuals to
`seek ophthalmological care. Regardless of the underlying etiology, dry eye has been shown to be
`associated with abnormalities in the pre-corneal tear film and subsequent inflammatory changes in the
`entire ocular surface including the adnexa, conjunctiva and cornea. Since the recognition of the role of
`inflammation in dry eye, a number of novel treatments have been investigated designed to inhibit
`various inflammatory pathways. Current medications that are used, including cyclosporine A,
`corticosteroids, tacrolimus, tetracycline derivatives and autologous serum, have been effective for
`management of dry eye and lead to measurable clinical improvement.
`Keywords: Keratoconjunctivitis Sicca, Sjӧgren’s Syndrome, Dry Eye, Inflammation, Treatment
`
`OVERVIEW
`Although often disregarded as a minor problem, keratoconjunctivitis sicca, commonly referred to as dry
`eye, is a growing public health concern affecting as many as 17% of women and 11.1% of men in the
`1
`United States. This is likely an underestimate if one also considers self-treating patients and
`milder/periodic cases with intermittent symptomatology.
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`Go to:
`
`A recent international Dry Eye Workshop (DEWS) defined dry eye as a “multifactorial disease of the
`tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film
`instability with potential damage to the ocular surface which is accompanied by increased osmolarity of
`2
`the tear film and inflammation of the ocular surface.” Identification of inflammation as a major factor
`in dry eye helped make a tremendous step forward in the description and treatment of this condition.
`
`The DEWS also recognized two subgroups of dry eye based on etiopathogenesis: aqueous deficient and
`evaporative. Among the aqueous deficient group, there are two major subclasses: Sjögren’s syndrome
`(SS) dry eye and non-SS dry eye. Diagnosis of SS is generally made based on the American-European
`Consensus Group 2002 revised classification criteria, requiring at least four out of six criteria, or three
`out of the four objective criteria, to be present. The six criteria include: subjective and objective ocular
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
`
`MYLAN - EXHIBIT 1094
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`Page 2 of 14
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`dryness; subjective and objective oral dryness; presence of Sjögren-specific antibody A (SSA)/Ro
`3
`and/or Sjögren-specific antibody B (SSB)/La; and positive minor salivary gland biopsy. However, in
`2012, a new classification criteria for SS was endorsed by The American College of Rheumatology that
`requires at least 2 of the following 3 criteria: 1) positive serum anti-SSA and/or anti-SSB or rheumatoid
`factor or antinuclear antibody (titer >1:320), 2) total ocular surface staining score >3, and 3) presence of
`4
`focal lymphocytic sialadenitis with a focus score >1/4 mm2 in labial salivary gland biopsy samples.
`
`According to the classification criteria from the European-American collaboration, secondary SS (sSS)
`consists of features of primary SS (pSS) together with features of an overt autoimmune connective
`tissue disease, the most common of which is rheumatoid arthritis. There is a well-known association of
`several systemic diseases with dry eye syndrome such as SS, rheumatoid arthritis, scleroderma,
`polymyositis, lymphoma, amyloidosis, hemochromatosis, sarcoidosis, and systemic lupus
`5
`erythematosus. Although the rate of dry eye in various inflammatory diseases is known, the frequency
`of associated systemic rheumatic conditions in patients with dry eye is currently unknown. A previous
`retrospective study from a single tertiary eye care center determined that pSS is underdiagnosed and
`should be the focus of diagnostic evaluations in individuals with clinically significant aqueous deficient
`dry eye. Only 33.3% of patients with pSS carried the diagnosis at the time of presentation and 50%
`6
`were diagnosed as a result of the initial evaluation. A more recent multicenter prospective study
`confirmed these findings in a group of more than 300 patients with clinically significant dry eye and
`7
`found the rate of SS to be 11.6%. The difference in the rate of SS between these two studies could
`perhaps be attributed to the fact that the prospective study was limited in regards to the diagnostic tests
`performed: minor salivary gland biopsy or tests for objective dry mouth findings were not utilized.
`Nonetheless, both studies concluded that ophthalmologists managing patients with clinically significant
`dry eye should have a high index of suspicion for underlying SS and a low threshold for diagnostic
`work-up.
`
`Previously unrecognized autoimmune thyroid disease has also been shown to be a cause of
`inflammatory ocular surface disease with dry eye symptomatology and should be considered when
`evaluating patients with dry eye. A retrospective, observational case series of 539 patients referred for
`dry eye evaluation has confirmed this correlation; of the 32 patients who underwent standardized orbital
`8
`echography with a clinical suspicion, 21 (66%) were diagnosed with occult thyroid eye disease.
`
`On the other hand, based on multiple epidemiological studies, older age and female sex are widely
`9,10
`recognized as the two most common risk factors for dry eye.
` Peri- and postmenopausal females
`seem to be particularly at a higher risk. This perhaps suggests that dry eye is an involutional disorder. In
`addition, hormonal studies demonstrate that sex hormones influence ocular surface conditions through
`their effects on aqueous tear secretion, meibomian gland function, and conjunctival goblet cell
`11,12
`density.
` Thus, an altered hormonal state (e.g., following menopause) may be blamed to cause dry
`eye. Several other external factors are also known to precipitate and exacerbate dry eye, such as long-
`term contact lens wear, refractive laser surgery, smoking, and extended visual tasks like computer use,
`13-15
`watching television and prolonged reading.
` Worsening of dry eye may also be attributed to low
`relative humidity conditions that are common in office environments, air-conditioned cars, airplane
`16
`cabins, and extreme hot or cold weather.
` Dry eye may be caused by systemic medications with
`17
`anticholinergic effects (e.g. antihistamines, antidepressants, antipsychotics) as well as diuretics.
`Frequent instillation (>4-6 times daily) of preserved eye drops, particularly with benzalkonium chloride
`for example for glaucoma, may also contribute to dry eye because of their well-established ocular
`17
`surface toxicity.
`
`Irrespective of the presence of any identifiable underlying local or systemic inflammatory disorder, dry
`eye seems to be invariably associated with chronic inflammation of the ocular surface, as detailed
`below, although it is not known whether the local inflammation is causative or simply occurs as a
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`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 3 of 14
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`consequence of ocular dryness. Nevertheless, recognition of the role of inflammation in dry eye has
`been a crucial factor in facilitating dry eye treatment.
`
`Go to:
`
`PATHOPHYSIOLOGY
`There is growing evidence from the past decade indicating that dry eye-related ocular surface
`18
`inflammation is mediated by lymphocytes.
` Based on earlier immuno-histopathological evaluations,
`patients with both SS-related as well as non-SS dry eye have identical conjunctival inflammation
`manifested by T cell infiltrates and upregulation of CD3, CD4, and CD8 as well as lymphocyte
`19
`activation markers CD11a and HLA-DR.
` These results suggested that clinical symptoms of dry eye
`may be dependent on T-cell activation and resultant autoimmune inflammation. Multiple other studies
`followed and demonstrated the role of pro-inflammatory cytokines and matrix metalloproteinases
`(MMPs) in the pathogenesis of dry eye. Interleukin (IL)-1 is one of the most widely studied cytokines
`accompanying dry eye. An increase in the pro-inflammatory forms of IL-1 (IL-1α and mature IL-1β)
`and a decrease in the biologically inactive precursor IL-1β have been found in the tear film of dry eye
`20
`patients.
` The source of increased levels of IL-1 was thought to be the conjunctival epithelium based
`20
`on immunohistochemical studies.
` More recently, reactive nitrogen species expressed by conjunctival
`21
`epithelium have been recognized in the pathogenesis or self-propagation of SS-related dry eye.
` In the
`same study, IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF) α were also investigated and found to
`play a significant role in SS-related dry eye as compared to normal eyes.
`
`The response of cells to extracellular stimuli such as ocular surface stress, including changes in the
`composition of tear film or hyperosmolarity and ultraviolet light exposure, is mediated in part by a
`22
`number of intracellular kinase and phosphatase enzymes.
` Mitogen-activated protein (MAP) kinases
`are integral components of parallel MAP kinase cascades activated in response to a number of cellular
`stresses including inflammatory cytokines (e.g. Il-1 and TNF-alpha), heat shock protein, bacterial
`endotoxin and ischemia. Activation of these MAP kinase homologues mediates the transduction of
`extracellular signals to the nucleus and is pivotal in regulation of the transcription events that determine
`functional outcomes in response to such stresses. These stress-activated protein kinases have been
`identified in the tear film of patients with dry eye. It has been documented that activation of these stress
`23
`pathways results in transcription of stress-related genes, including MMPs, mainly MMP-9.
` In another
`study, MAP kinases were found to stimulate the production of inflammatory cytokines including IL-β,
`24
`TNF-α, and MMP-9 and thereby cause ocular surface damage.
`
`As previously mentioned, hyperosmolarity is one of the factors contributing to ocular surface
`inflammation. Hyperosmolarity induces inflammation in human limbal epithelial cells by increasing
`expression and production of pro-inflammatory cytokines and chemokines such as IL-1β, TNF-α, and
`25
`the C-X-C chemokine IL-8.
` This process appears to be mediated through activation of the c-Jun
`N-terminal kinases and MAPK signaling pathways.
`
`All of these inflammatory mediators and pathways should not only be considered important as they
`relate to the pathogenesis of dry eye; they should also be kept in mind when discussing treatment
`strategies.
`
`TREATMENT
`As it is widely recognized that inflammation has a significant role in the etiopathogenesis of dry eye,
`promoting ocular surface disruption and symptoms of irritation, a number of anti-inflammatory
`treatments are currently in use for its management. Many more anti-inflammatory medications are in
`development or clinical trial phases. These agents inhibit the expression of inflammatory mediators on
`the ocular surface, thereby restoring the secretion of a healthy tear film and reducing signs and
`symptoms.
`
`Go to:
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 4 of 14
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`Cyclosporine A
`The immunomodulating effects of cyclosporine A are achieved through binding with cyclophilins,
`which are a group of proteins. Cyclophilin A which is found in the cytosol, and the cyclosporin
`e-cyclophilin A complex inhibits a calcium/calmodulin-dependent phosphatase, calcineurin, the
`inhibition of which is thought to halt the production of the transcription of T-cell activation by
`26
`inhibiting IL-2.
` Cyclophilin D is located in the matrix of mitochondria. Cyclosporine A-cyclophilin D
`complex modulates the mitochondrial permeability transition pore thereby inducing mitochondrial
`27
`dysfunction and cell death.
` The reduction in inflammation, via inhibition of T-cell activation and
`28,29
`down-regulation of inflammatory cytokines in the conjunctiva and lacrimal gland,
` is thus thought to
`30-32
`enhance tear production.
` Topical cyclosporine also increases goblet cell density and decreases
`33
`epithelial cell apoptosis.
` Commercially available topical cyclosporine 0.05% (Restasis, Allergan,
`Irvine, CA, USA) or 1% compounded preparations are frequently utilized for treatment of various
`34
`inflammatory ocular surface disorders.
` Dosing topical cyclosporine at a frequency greater than twice a
`day may be more effective for patients who do not demonstrate improvement of severe dry eye disease
`8,35
`with the twice-daily regimen.
`
`Go to:
`
`Tacrolimus
`This topical anti-inflammatory agent (previously known as FK506) is a macrolide antibiotic isolated
`36
`from Streptomyces tsukubaensis fermentation.
` Although the mechanism of action of tacrolimus is
`similar to cyclosporine A, its potency in vitro has been shown to be significantly greater, exhibiting
`37
`similar effects at 100 times lower concentrations.
` Only when bound to immunophilin does it become
`biologically active, thus effectively inhibiting calcineurin, and inhibiting T and B lymphocyte activation
`38-44
`via reduction in IL-2 synthesis.
` Tacrolimus suppresses the immune response by inhibiting the
`release of other inflammatory cytokines as well (e.g., IL-3, IL-4, IL-5, IL-8, interferon-gamma, and
`45-48
`TNF-alpha).
` Systemic tacrolimus has been reported to be effective for improving dry eye associated
`with graft versus host disease; however, there are potential adverse reactions to be aware of when
`49
`administering long-term systemic therapy.
` Topical tacrolimus, available as 0.03% and 0.1% ointments
`as well as compounded eye drops, is promising for the treatment of dry eye in the setting of chronic
`50-52
`graft versus host disease and SS.
`
`Go to:
`
`Corticosteroids
`Topical steroids, through several mechanisms of action, help reduce ocular inflammation.
`Corticosteroids function via suppression of cellular infiltration, capillary dilation, proliferation of
`fibroblasts, and collagen deposition. They stabilize intracellular and extracellular membranes.
`Corticosteroids increase the synthesis of lipocortins that block phospholipase A2 and inhibit histamine
`53
`synthesis in mast cells.
` Inhibition of phospholipase A2, an essential step in the inflammatory cascade,
`prevents the conversion of phospholipids to arachidonic acid. Corticosteroids also interfere with
`transcription factor NF-kB, which regulates the synthesis of a number of pro-inflammatory molecules,
`thereby stimulating lymphocyte apoptosis. Corticosteroids mediate their anti-inflammatory effects
`54,55
`primarily through modulation of the cytosolic glucocorticoid receptor at the genomic level.
` After
`corticosteroids bind to the glucocorticoid receptor in the cytoplasm, the activated corticosteroid-
`glucocorticoid receptor complex migrates to the nucleus, where it up-regulates the expression of anti-
`inflammatory proteins and represses the expression of pro-inflammatory proteins. However, recent
`work suggests that the activated corticosteroid-glucocorticoid receptor complex also elicits non-
`genomic effects, such as inhibition of vasodilation, vascular permeability and migration of
`54,56
`leukocytes.
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`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 5 of 14
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`Several clinical studies have demonstrated the effectiveness of topical steroids for treatment of dry eye.
`In a retrospective clinical series, topical administration of a 1% solution of non-preserved
`methylprednisolone, given three or four times daily for several weeks to patients with SS related dry
`57
`eye, provided moderate to complete relief of symptoms in all patients.
` In addition, there was a
`decrease in corneal fluorescein staining score (2.6±0.5 on a 12-point scale) and complete resolution of
`filamentary keratitis. This therapy was effective even for patients suffering from severe dry eye who
`had no improvement from maximum aqueous tear enhancement/replacement therapies.
`
`A pilot study on 64 patients was conducted evaluating the efficacy of loteprednol etabonate (LE) 0.5%
`ophthalmic suspension 4 times a day versus placebo for treatment of the inflammatory component of
`58
`dry eye associated with aqueous tear deficiency and delayed tear clearance.
` After 2 weeks of therapy
`in the subset of patients with moderate to severe clinical inflammation, a significant difference was
`observed between LE-treated group and vehicle-treated group in central corneal staining, nasal bulbar
`conjunctival hyperemia, and lid margin injection. None of the patients experienced a clinically
`significant increase in intraocular pressure following one month of therapy. Patients treated with topical
`corticosteroids should be monitored closely for known risks of cataract formation, glaucoma, corneal
`59
`thinning and infectious keratitis.
`
`Go to:
`
`Tetracycline Derivatives
`Tetracycline derivatives uniquely possess antibacterial as well as anti-inflammatory properties.
`Doxycyline has been shown to inhibit c-Jun N-terminal kinase and extracellular signal-related kinase
`mitogen-activated protein kinase signaling in epithelial cells of the ocular surface exposed to
`hyperosmolar stress, down-regulating the expression of CXCL8 and pro-inflammatory cytokines IL-1β
`60
`61,62
`and TNF.
` Doxycyline inhibits MMP-9 activity and supports ocular surface integrity.
` Additionally
`studies demonstrated that minocycline inhibits the expression of cell-associated pro-inflammatory
`63
`molecules, including major histocompatibility complex class II.
` Doxycycline has been reported to be
`effective in patients with ocular rosacea by reducing irritation symptoms, improving tear film stability,
`64-66
`and decreasing the severity of ocular surface disease.
` In addition, doxycycline has been useful in
`67,68
`the treatment of corneal erosions.
`
`Autologous Serum
`Serum contains several anti-inflammatory factors that have the capability to inhibit soluble mediators of
`the ocular surface inflammatory cascade associated with dry eye. These include inhibitors of
`inflammatory cytokines (e.g., IL-1 RA and soluble TNF-receptors) and MMP inhibitors (e.g.,
`69-71
`TIMPs).
` Clinical trials have shown that autologous serum drops improve ocular irritation
`symptoms, and conjunctival and corneal dye staining in dry eye that occurs in the setting of SS.
`Conversely, there is greater risk of microbial growth as autologous serum drops, in addition to
`75
`antimicrobial agents, contain high protein content and are generally non-preserved.
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`Go to:
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`72-74
`
`Recent studies have investigated cord serum drops (prepared from donor umbilical cord serum) as well
`as allogenic serum drops (from a related donor). A clinical trial included 17 patients with GVHD- and
`13 patients with SS-associated dry eye treated for 1 month with cord blood serum. Patients received
`cord blood once a day (containing 0.15 ng epithelial growth factor per drop). Patients reported a
`decrease in discomfort symptoms as measured with the Ocular Surface Disease Index score (OSDI)
`(22.3±10.3 vs. 39.3±16.9). Also clinical findings such as impression cytology score (3.8±1.2 vs.
`6.6±2.1), tear osmolarity (312.5±7 vs. 322±9.1 mOsm/L), and corneal sensation (measured with
`76
`Cochet-Bonnet esthesiometer) (48.2±2.1 vs. 49.7±2.1 nylon/mm/length) improved significantly.
`Another study involving 12 patients with chronic GVHD-associated severe dry eye treated with cord
`blood serum for a period of 6 months reported statistically significant improvement (P<0.01) in
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`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 6 of 14
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`symptom score (on a scale of 0-4, from 3.83±0.38 to 0.83±0.57), corneal sensitivity (from 52.08±6.06
`mm to 57.50±3.00 mm), tear breakup time (BUT) (from 2.50±0.91 to 5.71±1.04 seconds), and corneal
`77
`fluorescein staining (from 7.42±2.02 to 1.29±0.46).
` Also shown to be effective are allogenic serum
`drops, prepared using blood from a family member rather than the patient’s own blood. Allogeneic
`serum tears were used for the treatment of dry eye in patients with GVHD. After 4 weeks of continuous
`use, significant improvement was noted in symptom scores (as measured by OSDI Score from 32.5 to
`8.9), tear osmolarity (from 311.1 to 285.1 m osmol), corneal staining (from 2.5 to 1.8) as well as
`78
`increased goblet cell density (from 90.6 to 122.6 cell/mm2) and tear BUT (from 2.9 to 4.4 seconds).
`
`Go to:
`
`IL-Ra
`Interleukin-1 receptor antagonist (IL-1Ra) is an endogenous IL-1 receptor blocker primarily produced
`by activated monocytes and tissue macrophages which inhibits the activities of the pro-inflammatory
`79
`forms of IL-1 (IL-1α and IL-1β) by competitively binding to the IL-1 receptor-I.
` In a murine model
`with environmentally induced dry eye, a significant decrease in corneal fluorescein staining was
`observed with slit lamp biomicroscopy after topical treatment with 3 microliters of IL-Ra applied 3
`times daily for 9 days. Comparison treatments, 1% methylprednisolone and 0.05% cyclosporine A,
`80
`were equally effective in this model.
` Additionally, confocal microscopy revealed a significant
`decrease in the number of central corneal CD11b+ cells, lymphatic growth and interleukin-1β
`expression after treatment with 5% IL-1Ra and 1% methylprednisolone, but not with cyclosporine A.
`This suggests that IL-1Ra is comparable to topical methylprednisolone in reducing inflammation and
`improving clinical signs of dry eye.
`
`Go to:
`
`Resolvin E1 (Rx-10001)
`Resolvin E1 (RvE1) is a new class of endogenous immune response mediators derived from the
`lipoxygenation of the essential dietary omega-3 polyunsaturated fatty acids, eicosapentaenoic acid, and
`81
`docosahexaenoic acid.
` In animal models, treatment applied 4 times per day for one week, using
`topical 100μg/mL (0.01%) omega-3 derivatives has been shown to reverse corneal epithelial damage
`associated with dry eye. A specialized corneal tomography module (Rostock Cornea Module of the
`Heidelberg Retina Tomograph) was used to study the corneas in vivo. Increased tear flow promoting a
`healthy epithelium, decreased cyclooxygenase-2 expression by Western Blot Analysis, and decreased
`82
`macrophage infiltration were also noted.
` In a murine model of dry eye it was shown that RvE1,
`delivered topically at 300µg/ml concentration 4 times a day, improved corneal staining and goblet cell
`83
`density.
` The synthetic analog of RvE1 (RX-10045) is being tested in a Phase II clinical trial for
`treatment of chronic dry eye. Preliminary data of a 28-day, randomized, placebo-controlled, 232-patient
`84
`trial showed dose-dependent and statistically significant improvement using RX-10045;
` however,
`final data have not been published.
`
`Go to:
`
`Chemokine Receptor Antagonist
`Monocyte chemotactic protein 1 is secreted by monocytes, memory T cells, macrophages, fibroblasts,
`endothelial cells and mast cells. It stimulates the movement of leukocytes along a chemotactic gradient
`85
`after binding to its cell surface receptor chemokine receptor antagonist.
` The critical role of the
`coupled monocyte chemotactic protein 1/chemokine receptor antagonist in inflammation has been
`demonstrated using monocyte chemotactic protein 1 and chemokine receptor antagonist knockout mice,
`suggesting that inhibition of migration of chemokine receptor antagonist-bearing mononuclear cells
`86
`may be an effective mechanism to modulate disease progression in chronic inflammation.
` A study of
`dry eye disease in a murine model, which received topical chemokine receptor antagonist (5.0 mg/ml)
`twice daily for 7 days, showed a significant decrease in corneal fluorescein staining. Real-time
`polymerase chain reaction revealed decreased infiltration of corneal CD11b(+) cells and conjunctival T
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`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 7 of 14
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`87
` The chemokine receptor antagonist
`cells compared with vehicle treated and untreated dry eye groups.
`also significantly decreased messenger RNA expression levels of IL1-alpha and 1-beta in the cornea,
`and TNF-alpha and IL1-beta in the conjunctiva.
`
`Tofacitinib (CP-690,550)
`Tofacitinib (CP-690,550) is a selective inhibitor of the janus kinase (JAK). Janus kinase signaling is
`88
`essential for immune cell activation, pro-inflammatory cytokine production and cytokine signaling.
`Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular selectivity for JAK1 and
`89
`JAK3 over JAK2.
` Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common
`γ chain containing receptors for several cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. In
`addition, inhibition of JAK1 will result in attenuation of signaling by additional pro-inflammatory
`cytokines, such as IL-6 and interferon-γ. Tofacitinib subsequently modulates adaptive and innate
`90
`immunity with limited effect on hematopoiesis.
`
`Go to:
`
`In Phase I/II trials, topical tofacitinib (CP-690,550) at a concentration of 0.0003%-0.005% was used in
`327 patients with clinically significant aqueous deficient dry eye for a period of 8 weeks. A trend for
`improving both signs (Schirmer’s test without anesthesia and corneal fluorescein staining) and
`91
`symptoms of dry eye, with a reasonable safety profile was noted.
` In addition, a sub-study of Phase I/II
`trials showed a reduction in inflammation assessed by change from baseline in conjunctival cell surface
`expression of human leukocyte antigen DR-1 studied by flow cytometry and tear levels of several
`92
`cytokines and inflammation markers by microsphere-based immunoassays.
`
`Go to:
`
`SAR 1118 (LFA-1 antagonist)
`SAR 1118, a novel investigational small-molecule lymphocyte function-associated antigen-1
`93,94
`antagonist, was engineered for topical ophthalmic delivery.
` The binding of lymphocyte function-
`associated antigen-1 on the surface of T cells to intercellular adhesion molecule-1 on endothelial,
`epithelial, and antigen presenting cells is a critical step in T-cell activation (normal immune response
`and inflammation). Thus, it has been proposed that blockade of lymphocyte function-associated
`antigen-1/intercellular adhesion molecule-1 interaction may give a therapeutic benefit in patients with
`dry eye, breaking the chronic cycle of T-cell mediated inflammation and thus aiding in the recovery of
`the ocular surface. SAR 1118 is an effective inhibitor of T-cell activation, adhesion, migration,
`93
`proliferation and cytokine release.
` A multicenter, prospective, double-masked, placebo-controlled
`trial included 230 dry-eye subjects randomized to receive SAR 1118 (0.1, 1.0, 5.0%) or placebo eye
`drops twice daily for 84 days. SAR 1118 showed dose-dependent and statistically significant
`improvement in corneal staining scores, symptoms measured with OSDI (both total ocular surface
`disease index and visual related function questions) as compared to placebo. Improvements in tear
`production and symptoms were noted as early as day 14. It was well tolerated and no serious ocular
`94
`adverse events were reported.
` Several Phase III trials are underway and results are yet to be published.
`
`Mapracorat
`Mapracorat (formerly ZK-245186 and subsequently BOL-303242-X) is a novel selective glucocorticoid
`receptor agonist currently under investigation for its anti-inflammatory effects as it pertains to dry eye.
`The anti-inflammatory effects of mapracorat were assessed in an in vitro osmotic stress model which
`95
`simulates some of the pathophysiological changes seen in dry eye.
` Incubation of cells with
`mapracorat 0.1-1.0% applied 3 times a day for 7-8 days inhibited hyperosmolar-induced cytokine
`release with comparable activity and potency as a commonly used steroid, dexamethasone. In addition,
`another study observed mapracorat to be effective in maintaining tear volume and tear break-up time
`96
`with no increase in intraocular pressure in a rabbit model.
`
`Go to:
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181208/
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`Page 8 of 14
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`SUMMARY
`Regardless of whether or not an underlying systemic inflammatory condition can be identified, dry eye
`seems to be associated with chronic and sometimes subclinical inflammation that might eventually
`cause ocular surface damage. Novel treatments targeting specific mediators in inflammatory reactions
`known to be associated with dry eye are currently evolving.
`
`Go to:
`
`Footnotes
`Conflicts of Interest
`This study was supported in part by Jerome L. Greene Discovery Fund. Dr. Akpek has received institutional
`research grants from Alcon and Allergan Inc. as well as National Institutes of Health (ID#: 107364) in the past 2
`years. Dr. Akpek has received ad hoc consultant income from Bausch & Lomb.
`
`Go to:
`
`REFERENCES
`1. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol.
`2000;118:1264–1268. [PubMed]
`
`Go to:
`
`2. The definition and classification of dry eye disease: report of the definition and classification
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